Alzheimer's disease (AD) is a progressive disease known generally as senile dementia. The disease falls into two categories, namely late onset and early onset. One form of this latter AD type runs in families and it is known as familial AD.
Both types of AD are characterized by two types of lesions in the brain: senile plaques and neurofibrillary tangles. Senile plaques are areas of disorganized neuropil up to 150 mm across with extracellular amyloid deposits at the center. Neurofibrillary tangles are intracellular deposits consisting of two filaments twisted about each other in pairs.
Aβ also referred to as amyloid β peptide (AβP) is a highly aggregating small polypeptide having a molecular weight of approximately 4,500. This protein is a cleavage product of a much larger precursor protein referred to as amyloid precursor protein (APP). The Aβ protein comprises 39–42 amino acids (SEQ ID NO:1). There are at least five distinct isoforms of APP: 563, 695, 714, 751, and 770 amino acids, respectively (Wirak et al. (1991)). The Aβ protein segment comprises approximately half of the transmembrane domain and approximately the first 28 amino acids of the extracellular domain of an APP isoform.
APP is a transmembrane protein which is highly expressed in all parts of the body, and which has several important biological functions. Proteolytic processing of APP in vivo is a normal physiological process. Carboxy-terminal truncated forms of APP695, APP751, and APP770 are present in brain and cerebrospinal fluid (Palmert et al. (1989)) (Weidemann et al (1989)). There are probably two main metabolic pathways; one non-amyloid-forming and one amyloid-forming pathway. The amyloid forming non-normal pathway produces the Aβ protein polypeptide which is prone to form dense amyloidogenic aggregates that are resistant to proteolytic degradation and removal. The resultant Aβ protein aggregates presumably are involved in the formation of the abundant amyloid plaques and cerebrovascular amyloid that are the neuropathological hallmarks of AD.
In AD brains, the Aβ peptide forms virtually insoluble amyloid fibrils that accumulate into senile plaques. The Aβ fibrillization process is a complex multistep reaction. A group of distinct intermediary Aβ species of the fibrillization reaction, the protofibrils, were recently identified (Walsh et al. (1997)), (Walsh et al. (1999), (Harper et al,(1999)).
The most common Aβ form in cerebrospinal fluid (CSF) and plasma comprises 40 amino acids (Aβ40), but an Aβ comprising 42 amino acids (Aβ42) is the most common form in plaques (Scheuner et al. (1996)). This longer form tends to aggregate more rapidly and it is believed that it is more pathogenic than Aβ40.
Many patients get Alzheimer's disease spontaneously with unknown ethiology, but there are also several hereditary components involved. Disease-causing mutations in genes on chromosomes 1, 14, and 21, respectively, have been discovered, and these mutations might explain as much as 50% of disease forms starting very early (<50 years)(St. George-Hyslop et al. (1987), (Sherrington et al. (1995)).
The first gene associated with Alzheimer's disease was the gene encoding the amyloid precursor protein APP on chromosome 21. Different mutations of this gene result in unusual hereditary forms of the disease. Several pathogenic mutations have been identified in the (APP) gene, all located close to the major APP processing sites. These processing sites are either located adjacent to the boundaries of the Aβ domain in APP (the β- and γ-secretase sites) or within the Aβ sequence itself (α-secretase site).
The only known AD mutation close to the β-secretase site, the Swedish mutation (Mullan, et al., (1992)), discloses a double mutation (Lys670Asn/Met67ILeu) of the APP gene in a large Swedish family, in which family the disease starts early and has a high penetrating power. The mutation produces a large increase of Aβ production, an elevation of both Aβ42 and Aβ40 in plasma from mutation carriers and in conditioned cell media.
Other APP mutations have been described. All result in Alzheimer's disease with, an early age of onset having an autosomal dominant heredity pattern. Pathogenic mutations within the Aβ sequences located close to the α-secretase site, result in a phenotype different from AD, with massive amyloid accumulation in cerebral blood vessel walls. Two mutations at codons 692 and 693, namely the Dutch (Glu693Gln) and the Flemish (Ala692Gly) mutations, have been reported (Levy et al. (1990)), (van Broeckhoven et al. (1990)), (Hendriks et al. (1992)). Patients having these mutations suffer from cerebral haemorrhage and vascular symptoms. The vascular symptoms are caused by aggregation of Aβ in blood vessel walls (amyloid angiopathy). A third pathogenic intra-Aβ mutation was recently discovered in an Italian family (E693K), with clinical findings similar to the Dutch patients (Tagliavini, et al. (1999)).
Different pathogenic mechanisms have been proposed for the Dutch and Flemish mutations. It has been observed that the Flemish mutation leads to increased Aβ levels while a reduced ratio of Aβ42/40 was seen in media from cells transfected with the Dutch mutation (De Jonghe, et al. (1998)). Investigations of synthetic Aβ peptides have indicated that the Dutch mutation, but not the Flemish, accelerates the fibril formation compared to wild-type (wt) peptide (Walsh et al. (1997)).
As reported by Kamino et al. 1992, another APP E693 variant wherein Glu is substituted for Gly at APP E693, has previously been seen in one individual. It could not be unambiguously determined to be responsible for AD, though. This case originated from a family with similar clinical characteristics for AD and definitive AD was confirmed at autopsy. However, in this family the mutation could only be detected in one of two demented siblings.
Mice transgenic for APP mutations show many of the pathological features of Alzheimer disease, including deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. In recent studies by (Schenk et al (1999)) it was reported that immunization with Aβ42 wild-type peptide is both preventive in transgenic mice, but also that Aβ containing plaques can be greatly reduced in the brain of transgenic mice immunized with the peptide.
However, due to the large costs and suffering that are associated with Alzheimer's disease, there is still a need for improved methods for treatment and prevention thereof.
Likewise, there is a need For a method for screening compounds that could constitute a part of future pharmaceutical preparations for treating and perhaps curing Alzheimer's disease.